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Ferritin heavy polypeptide 1 (FTH1) plays a pivotal role in response to viral infections. FTH1 expression is modulated by various pathogens, but the regulatory mechanisms are unknown. We firstly construct duck hepatitis virus 1 (DHV-1) infection model, including morbid ducklings, non-morbid ducklings and control ducklings. Then the mRNA expression of duck FTH1 (duFTH1) was measured mRNA expression of duck FTH1 (duFTH1) in the liver and spleen after duck hepatitis virus 1 (DHV-1) infection using quantitative polymerase chain reaction (qPCR) and found that duFTH1 mRNA was down-regulated significantly in morbid ducklings (liver, P < 0.01; spleen, P < 0.05) compared with the control ducklings. We also found that duFTH1 expression was significantly higher in the spleen (P < 0.01) and liver (P < 0.05) of non-morbid ducklings than in morbid ducklings. Moreover, DNA methylation of the duFTH1 promoter was examined by bisulfite sequencing (BSP) and we found that the duFTH1 promoter was hypomethylated, the relative methylation was only 5.9% and 2.0% in the morbid ducklings and non-morbid ducklings, respectively. The promoter contained a −55 C/T mutation in 75% of non-morbid ducklings, and this polymorphism affected promoter activity. Further analysis suggested that this mutation altered the binding site of the transcription factor NRF1. Binding of NRF1 to the FTH1 promoter was confirmed by electrophoretic mobility shift assay (EMSA) analysis. Thus, our findings revealed the NRF1 was a negative regulator, and lossed of binding of NRF1 to duFTH1 promoter due to −55C/T mutation enhances duFTH1 expression in non-morbid ducks, which provided molecular insights into the effect of duFTH1 expression via promoter polymorphisms, but not DNA methylation, in response to DHV-1 challenge.The FTH1 expression was regulated in ducks during DHV-1 challenge by a mutation that alters a NRF1 binding site.Our results revealed that the −55T allele of the FTH1 promoter region markedly enhanced FTH1 transcription.There was no evidence that DNA methylation of the FTH1 promoter region contributed to the regulation of FTH1 expression.